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cytoskeleton ͉ thymus ͉ migration ͉ colitis ͉ knockout mice L ymphoid progenitors enter the thymus to initiate a complex differentiation process resulting in maturation of T cells (1, 2). The well characterized maturation steps of ␣␤ T cells in the thymus are also governed by trafficking events and positional cues driven by guidance molecules, including chemokines, adhesion molecules, and extracellular matrix components (3-6). Rearrangement of the actin cytoskeleton is regulated during both T cell receptor signaling and T cell migration (7-9), but much less is known about its requirement during T cell development. The small Rho-family GTPases and their guanine nucleotide exchange factors (GEFs), proteins known to regulate the actin cytoskeleton, are clearly required during thymocyte development (10-12). Although these molecules are also known to regulate cell adhesion and migration, their involvement in thymocyte trafficking has not been thoroughly assessed. The small GTPase effector molecule Wiskott-Aldrich syndrome protein (WASP) has also been demonstrated to be a critical regulator of antigen receptor signaling, actin cytoskeletal rearrangements, and lymphocyte migration (13-22). Although WASP deficiency has been correlated with lower numbers of naïve T cells (23), WASP does not seem to play a critical role in T cell development. Moreover, despite a large body of evidence showing a role for WASP in T cell signaling, its role in thymocyte migration has not been studied. WASP belongs to the WASP family of proteins, including WASP, N-WASP, and WAVE/SCAR molecules 1-3 (24). In particular, N-WASP, which shares 50% homology with WASP, may serve specific and redundant function with WASP in hematopoietic cells. In fact, we have shown that expression of N-WASP in WASP-deficient T cells partly restores CD3-mediated proliferation, implying that WASP and N-WASP might share functions in T cells (25).Here we sought to explore the importance of cytoskeletal regulation for thymocyte development by examining the unique and redundant roles of WASP and N-WASP. Using two complementary approaches, we analyzed T cells devoid of WASP and N-WASP and demonstrated that thymopoiesis cannot proceed in the absence of WASP and N-WASP. Results Deletion of WASP and N-WASP in Lymphocytes Using the RAG-2-Deficient Complementation System Leads to a Block in T Cell Development.We have demonstrated that lymphoid development is normal in WASP knockout (WKO) mice (20). We hypothesized that N-WASP might have some overlapping functions with WASP during lymphopoiesis and sought to investigate the unique and redundant activities for WASP and N-WASP in T cell development and function. To circumvent the embryonic lethality of N-WASP germ-line inactivation in mice (26), we used the RAG2-deficient blastocyst complementation system (27). Blastocysts from RAG-2-deficient mice implanted into foster mothers generate animals that fail to rearrange antigen receptor genes and consequently lack mature B and T cells. Injection of gene-targeted ES cells into RAG-2-...

T cell antigen recognition involves the formation of a structured interface between antigen-presenting and T cells that facilitates the specific transmission of activating and desensitizing stimuli. The molecular machinery that organizes the signaling molecules and controls their disposition in response to activation remains poorly understood. We show here that in T cells Discs large (Dlg1), a PDZ domain-containing protein, is recruited upon activation to cortical actin and forms complexes with early participants in T cell activation. Transient overexpression of Dlg1 attenuates basal and Vav1-induced NFAT reporter activation. Reduction of Dlg1 expression by RNA interference enhances both CD3- and superantigen-mediated NFAT activation. Attenuation of antigen receptor signaling appears to be a complex, highly orchestrated event that involves the mutual segregation of important elements of the early signaling complex.

BACKGROUND: Although studies of metastasectomy have been limited primarily to institutional experiences, reports of favorable long-term outcomes have generated increasing interest. In the current study, the authors attempted to define the national practice patterns in metastasectomy for 4 common malignancies with varying responsiveness to systemic therapy. METHODS: The National (Nationwide) Inpatient Sample was used to estimate the national incidence of metastasectomy for colorectal cancer, lung cancer, breast cancer, and melanoma from 2000 through 2011. Incidence-adjusted rates were determined for liver, lung, brain, small bowel, and adrenal metastasectomies. The average annual percentage change (AAPC) in metastasectomy by cancer type was calculated using joinpoint regression. RESULTS: Colorectal cancer was the most common indication for metastasectomy (87,407 cases; 95% confidence interval [95% CI], 86,307-88,507 cases) followed by lung cancer (58,245 cases; 95% CI, 57,453-59,036 cases), breast cancer (26,271 cases; 95% CI, 25,672-26,870 cases), and melanoma (20,298 cases; 95% CI, 19,897-20,699 cases). Metastasectomy increased significantly for all cancer types over the study period: colorectal cancer (AAPC, 6.83; 95% CI, 5.7-7.9), lung cancer (AAPC, 5.8; 95% CI, 5.1-6.4), breast cancer (AAPC, 5.5; 95% CI, 3.7-7.3), and melanoma (AAPC, 4.03; 95% CI, 2.1-6.0). Despite an increasing number of comorbidities in patients undergoing metastasectomy (P<.05 for each cancer type), inpatient mortality rates after metastasectomy fell for all cancer types, most significantly for colorectal (AAPC, 25.49; 95% CI, 28.2 to 22.7) and lung (AAPC, 26.2; 95% CI, 211.7 to 20.3) cancers. The increasing performance of metastasectomy was largely driven by high-volume institutions, in which patients had a lower mean number of comorbidities (P<.01 for all cancer types) and lower inpatient mortality (P<.01 for all cancers except melanoma). CONCLUSIONS: From 2000 through 2011, the performance of metastasectomy increased substantially across common cancer types, notwithstanding various advances in systemic therapies. Metastasectomy was performed more safely, despite increasing patient comorbidity. High-volume institutions appeared to drive practice patterns. Cancer 2015;121:747-57. V C 2014 American Cancer Society.KEYWORDS: metastasectomy, colorectal cancer metastasectomy, lung cancer metastasectomy, breast cancer metastasectomy, melanoma metastasectomy, surgical trends. INTRODUCTIONHistorically, the role of surgery in patients with metastatic cancer was predominately limited to palliative or emergent operations. By the 1980s, however, a few centers were consistently performing surgical resections for select patients with metastatic cancer and reporting promising results. [1][2][3] In addition, theories of cancer biology began to suggest that in a subset of patients, oligometastatic disease might indeed represent the entire clinically relevant disease burden. 4 In these cases, complete resection was associated with prolonged disease-free s...